CN105102425A - Process for preparing bile acid derivatives - Google Patents
Process for preparing bile acid derivatives Download PDFInfo
- Publication number
- CN105102425A CN105102425A CN201380068062.XA CN201380068062A CN105102425A CN 105102425 A CN105102425 A CN 105102425A CN 201380068062 A CN201380068062 A CN 201380068062A CN 105102425 A CN105102425 A CN 105102425A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- acceptable salt
- pharmacy acceptable
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 27
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical class C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 274
- 238000000034 method Methods 0.000 claims abstract description 153
- 150000003839 salts Chemical class 0.000 claims abstract description 102
- 239000012453 solvate Substances 0.000 claims abstract description 27
- 230000008569 process Effects 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims description 81
- 239000001257 hydrogen Substances 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 14
- 239000007789 gas Substances 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 241000872931 Myoporum sandwicense Species 0.000 claims description 8
- 230000002829 reductive effect Effects 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 59
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- 239000003880 polar aprotic solvent Substances 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
- 239000011541 reaction mixture Substances 0.000 description 40
- 239000000203 mixture Substances 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 27
- 239000002904 solvent Substances 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- 229910052799 carbon Inorganic materials 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical group O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000003513 alkali Substances 0.000 description 13
- 229940093499 ethyl acetate Drugs 0.000 description 13
- -1 C23 carboxylic acid Chemical class 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 11
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical group CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000000284 extract Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 8
- 150000008065 acid anhydrides Chemical class 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 230000005587 bubbling Effects 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 150000004678 hydrides Chemical class 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical group O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 5
- 150000002431 hydrogen Chemical group 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000012266 salt solution Substances 0.000 description 5
- 239000000126 substance Chemical group 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 229960003328 benzoyl peroxide Drugs 0.000 description 4
- 235000010290 biphenyl Nutrition 0.000 description 4
- 239000004305 biphenyl Substances 0.000 description 4
- 238000010504 bond cleavage reaction Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 230000000155 isotopic effect Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229960001661 ursodiol Drugs 0.000 description 3
- HGBGABMSTHQFNJ-UHFFFAOYSA-N 1,4-dioxane;sulfur trioxide Chemical compound O=S(=O)=O.C1COCCO1 HGBGABMSTHQFNJ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- 229910010082 LiAlH Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical compound CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 238000006277 sulfonation reaction Methods 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N C1CC=CCC1 Chemical compound C1CC=CCC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 1
- XNPZNZSQFBQSTE-UHFFFAOYSA-N CCCC(C1)C1N Chemical compound CCCC(C1)C1N XNPZNZSQFBQSTE-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- 238000005485 electric heating Methods 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to processes for preparing compounds of formula I: or a pharmaceutically acceptable salt or solvate thereof.
Description
the cross reference of related application
This application claims right of priority and the rights and interests of the U.S. Patent application 61/718,966 that on October 26th, 2012 submits to, its full content is incorporated herein by reference.
summary of the invention
The present invention relates to the compound of preparation formula I
Or the method for its pharmacy acceptable salt or solvate, wherein
Represent that substituting group is in α or β stereochemistry at the dotted line key of the 7th (----);
R is hydrogen or hydroxyl; And
R
1for hydrogen or C
1-C
6alkyl.
Unless otherwise defined, otherwise all technology used herein and scientific terminology all have the identical meanings that those skilled in the art generally understand.If clashed, should be as the criterion with this specification sheets (comprising definition).In this manual, unless the context clearly indicates otherwise, otherwise singulative also comprises plural form.Although can use similar in enforcement of the present invention or test or be equivalent to method as herein described and material, the method that following description is applicable to and material.All announcements mentioned in this article, patent application, patent and other reference are incorporated herein by reference.Do not admit that the reference quoted is the prior art of invention required for protection herein.In addition, material, method and embodiment are only illustrative, and are not intended to be restriction.
By following detailed description and claim, other features and advantages of the present invention will be apparent.
accompanying drawing is sketched
Fig. 1: from the HPLC chromatogram of the compound VI IA that embodiment 2 obtains.
Fig. 2: the compound VI IA's obtained from embodiment 2
1hNMR composes.
detailed Description Of The Invention
The present invention relates to the compound of preparation formula I
Or the method for its pharmacy acceptable salt or solvate, wherein
Represent that substituting group is in α or β stereochemistry at the dotted line key of the 7th (----);
R is hydrogen or hydroxyl; And
R
1for hydrogen or C
1-C
6alkyl.
In one aspect, in four-step method, can from the compound of formula II the compound of preparation formula I or its pharmacy acceptable salt or solvate.Square case 1.The preparation of raw material 6 α-ethyl-5 β-ursodeoxycholic acid is disclosed in EP1392714 and EP1568706.
scheme 1
Steps A is the hydroxyl of protection in C3 and the C7 position of formula II compound, and the Grignard reaction of production 3A compound.Step B is the oxidation scission of the double bond of formula 3A compound, to obtain the compound of formula 4A.Step C is the C23 carboxylic acid of reduction-type 4A compound, to obtain the compound of formula 5A.Step D is the C23 hydroxyl of sulfonation formula 5A compound, to obtain the salt of formula I-Na.The salt of formula I-Na can be made to change into its free alkali form (that is, the compound of formula I) or other salt form (such as, formula I-(Et)
3the salt of NH).
In one aspect, in six one step process, can from the compound of formula II the compound of preparation formula I or its pharmacy acceptable salt or solvate.Square case 2.
scheme 2
The compound that step 1 is esterification formula II, to obtain the compound of formula III.Step 2 is Grignard reaction, with the compound of the compound of formula IV from formula III.Step 3 is the hydroxyl of protection in the C3 position of formula IV compound, to obtain the compound of formula V.Step 4 is oxidation scission and the C7 hydroxyl oxidize of the double bond of formula V compound, to obtain the compound of formula VI.Step 5 is C23 carboxylic acid and the C7 carbonyl of reduction-type VI compound, to obtain the compound of formula VII.The C23 hydroxyl that step 6 is sulfonation formula VII compound, to obtain the salt of formula I-Na.The salt of formula I-Na can be made to change into its free alkali form (that is, the compound of formula I) or other salt form (such as, formula I-(Et)
3the salt of NH).
In scheme 2 step 4, generate C7 ketone group in oxidation scission (such as, utilizing ruthenium) period, this is competitive side reaction.By using Ac in scheme 2 step 3 in methylene dichloride
2o and Bi (OTf)
3protection C7 hydroxyl, together with C3 hydroxyl, can avoid this competitive side reaction.
Synthetic compound IA
Method be disclosed in United States Patent (USP) 7,932,244 (being referred to herein as ' 244 patents).Square case 3.
scheme 3
Although Compound I A can be prepared (being equivalent to compound 10 in scheme 3) according to the method for ' 244 patents, more effective synthetic route is necessary to industrial-scale production.Method of the present invention openly allows more effective route of the compound of formula I of industrial-scale production (such as, Compound I A).Method of the present invention (scheme 1 or scheme 2) is conducive to currently known methods disclosed in ' 244 patents (scheme 3).' 244 patents disclose eight one step process, and the present invention is only the four-step method of scheme 1 or six one step process of scheme 2.For Compound I A, according to scheme 2, the overall yield of the inventive method is at least 46%, be 45%, and the productive rate of ' 244 patents is about 7% according to scheme 1.Method of the present invention needs less step, and the productive rate providing essence higher, this allows the compound of large-scale industry synthesis type I.Method of the present invention utilizes the method that is different from ' 244 patents and the scission of link being different from ' 244 patents and becomes key step.
the method of scheme 1
In one aspect, the present invention relates to the compound of preparation formula I
Or the method for its pharmacy acceptable salt or solvate, wherein
Represent that substituting group is in α or β stereochemistry at the dotted line key of the 7th (----);
R is hydrogen or hydroxyl; And
R
1for hydrogen or C
1-C
6alkyl,
Said method comprising the steps of:
Steps A: the compound making the converting compounds accepted way of doing sth 3A of formula II:
;
Step B: the compound making the converting compounds accepted way of doing sth 4A of formula 3A:
;
Step C: the compound making the converting compounds accepted way of doing sth 5A of formula 4A:
; With
Step D: the compound making the converting compounds accepted way of doing sth I-Na of formula 5A:
。
In one aspect, the present invention relates to the compound of preparation formula I or the method for its pharmacy acceptable salt, wherein R is hydroxyl.In yet another aspect, R is hydrogen.In one aspect, R
1for C
1-C
6alkyl.In one aspect, R
1for methyl.In yet another aspect, R
1for ethyl.In yet another aspect, R
1for propyl group.In yet another aspect, R is hydrogen, and R
1for C
1-C
6alkyl.In yet another aspect, R is hydroxyl, and R
1for C
1-C
6alkyl.In yet another aspect, R is hydrogen, and R
1for C
1-C
3alkyl.In yet another aspect, R is hydroxyl, and R
1for C
1-C
3alkyl.
In one aspect, the present invention relates to the compound of preparation formula I or the method for its pharmacy acceptable salt or solvate, wherein said salt is selected from
。
In one aspect, the present invention relates to the compound of preparation formula I or the method for its pharmacy acceptable salt or solvate, wherein said salt is selected from
。
step B
In one aspect, the present invention relates to the compound of preparation formula I
Or its pharmacy acceptable salt (such as, formula IA, IB, IC, ID, IAA, IBB, ICC and IDD any one) or the method for solvate, wherein
Represent that substituting group is in α or β stereochemistry at the dotted line key of the 7th (----);
R is hydrogen or hydroxyl; And
R
1for hydrogen or C
1-C
6alkyl,
Said method comprising the steps of:
Step B: the compound making the converting compounds accepted way of doing sth 4A of formula 3A:
。
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in stepb, make compound and the RuCl of formula 3A
3, NaIO
4and acid-respons, with the compound of production 4A.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in stepb, the compound of formula 3A and RuCl
3mol ratio be about 18:1 to about 22:1.In yet another aspect, this mol ratio is about 19:1 to about 21:1.In yet another aspect, this mol ratio is about 20:1.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in stepb, acid is H
2sO
4, HCl, HClO
4or HIO
4.In yet another aspect, acid is 2NH
2sO
4.In yet another aspect, acid is 2NHCl.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in stepb, compound and the mol ratio of acid of formula 3A are about 1:1 to about 4:1.In yet another aspect, this mol ratio is about 1:1 to about 3:1.In yet another aspect, this mol ratio is about 2:1.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in stepb, react and carry out in the mixture of solvent.In one aspect, the mixture of solvent comprises a kind of polar aprotic solvent and two kinds of polar aprotic solvents.In one aspect, polar aprotic solvent is H
2o.In one aspect, polar aprotic solvent is acetonitrile and ethyl acetate.In one aspect, polar aprotic solvent is acetonitrile and chloroform.In one aspect, the mixture of solvent is H
2o/ ethylacetate/acetonitrile or H
2o/ chloroform/acetonitrile.
In one aspect, H
2o: ethyl acetate: the ratio of acetonitrile is that about 1:1:1 is to about 1:3:2 volume ratio.In yet another aspect, this is than being about 1:1.5:1 extremely about 1:2.5:1.5 volume ratio.In one aspect, this is than being about 1:2:1.5 volume ratio.
In one aspect, the mixture of solvent comprises a kind of polar aprotic solvent and a kind of polar aprotic solvent.In one aspect, polar aprotic solvent is H
2o.In one aspect, polar aprotic solvent is chloroform, acetonitrile or acetone.In one aspect, the mixture of solvent is H
2o/ chloroform, H
2o/ acetonitrile or H
2o/ acetone.
In one aspect, the mixture of solvent comprises two kinds of polar aprotic solvents.In one aspect, polar aprotic solvent is H
2o and the trimethyl carbinol.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in stepb, the temperature of reacting at about-10 DEG C to about 10 DEG C is carried out.In one aspect, temperature is about-5 DEG C to about 5 DEG C.In one aspect, temperature is about 0 DEG C.
step BX
In one aspect, the step B in step BX alternative scheme 1.In one aspect, the present invention relates to the compound of preparation formula I
Or its pharmacy acceptable salt (such as, formula IA, IB, IC, ID, IAA, IBB, ICC and IDD any one) or the method for solvate, wherein
Represent that substituting group is in α or β stereochemistry at the dotted line key of the 7th (----);
R is hydrogen or hydroxyl; And
R
1for hydrogen or C
1-C
6alkyl,
Said method comprising the steps of:
Step BX: the compound making the converting compounds accepted way of doing sth 4A of formula 3A:
。
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step BX, make compound and the O of formula 3A
3solid/liquid/gas reactions, with the compound of production 4A.In one aspect, O
3gas also comprises O
2gas.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step BX, make gas pass through reaction mixture with about 4psi to about 15psi bubbling.In another embodiment, gas passes through reaction mixture with about 10psi to about 15psi bubbling.In another embodiment, gas passes through reaction mixture with about 12psi bubbling.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step BX, react and carry out in polar aprotic solvent.In one aspect, polar aprotic solvent is methylene dichloride.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step BX, the temperature of reacting at about-73 DEG C to about-78 DEG C is carried out.
step D
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, said method comprising the steps of:
Step B: the compound making the converting compounds accepted way of doing sth 4A of formula 3A:
; With
Step D: the compound making the converting compounds accepted way of doing sth I-Na of formula 5A:
。
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step D, the compound of formula 5A and sulphonating agent are reacted, with the salt of production I-Na.In one aspect, sulphonating agent is sulphur trioxide, chlorsulfonic acid or thionamic acid.In yet another aspect, sulphonating agent is sulfur trioxide complex.In yet another aspect, sulfur trioxide complex is selected from sulfur trioxide pyridine, sulphur trioxide dioxane and sulfur trioxide trimethylamine.In yet another aspect, sulfur trioxide complex is sulfur trioxide pyridine.
In one aspect, the mol ratio of sulphonating agent and formula 5A compound is about 4:1 to about 1:1.In yet another aspect, this mol ratio is about 3:1 to about 1.5:1.In yet another aspect, this mol ratio is about 2:1.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step D, react and carry out in polar aprotic solvent.In yet another aspect, polar aprotic solvent is pyridine.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step D, the temperature of reacting at about 10 DEG C to about 30 DEG C is carried out.In one aspect, temperature is about 15 DEG C to about 25 DEG C.In yet another aspect, temperature is about 20 DEG C to about 23 DEG C.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step D, reaction mixture under an inert atmosphere.In yet another aspect, inert atmosphere is nitrogen atmosphere.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step D, during aftertreatment, carry out the resistates of reaction mixture with alkali and polar aprotic solvent process.In one aspect, polar aprotic solvent is C
1-C
6alcohol.In one aspect, polar aprotic solvent is C
1-C
3alcohol.In one aspect, polar aprotic solvent is CH
3oH.In one aspect, alkali is NaOH.In one aspect, alkali is CH
310% (w/w) solution of NaOH in OH.
step C
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, said method comprising the steps of:
Step B: the compound making the converting compounds accepted way of doing sth 4A of formula 3A:
;
Step C: the compound making the converting compounds accepted way of doing sth 5A of formula 4A:
; With
Step D: the compound making the converting compounds accepted way of doing sth I-Na of formula 5A:
。
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step C, the compound of formula 4A and reductive agent are reacted, with the compound of production 5A.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, described method is included in further in step C and makes the compound of formula 4A and a kind of reaction reaction, with the acid anhydride of the compound of production 4A.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, described method is included in step C the compound and chloro-formic ester reagent and alkali reaction that make formula 4A further, with the acid anhydride of the compound of production 4A.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, described method is included in further in step C and makes the acid anhydride of the compound of formula 4A and a kind of reaction reaction, with the compound of production 5A.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, described method is included in step C acid anhydride and the hydride reaction of the compound making formula 4A further, with the compound of production 5A.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step C, hydride is NaBH
4, Na/t-BuOH, LiAlH
4, NaAlH
2(OC
2h
4oCH
3)
2or LiBH
4.In yet another aspect, hydride is NaBH
4.
In one aspect, NaBH
4be about 50:1 to about 60:1 with the mol ratio of formula 4A compound.In yet another aspect, this mol ratio is about 54:1 to about 57:1.In yet another aspect, this mol ratio is about 56:1.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step C, chloro-formic ester reagent is isobutyl chlorocarbonate, Vinyl chloroformate, isopropyl chlorocarbonate or isobutylchloroformate.In one aspect, chloro-formic ester reagent is isobutyl chlorocarbonate.
In one aspect, the mol ratio of isobutyl chlorocarbonate and formula 4A compound is about 1:1 to about 1.5:1.In yet another aspect, mol ratio is about 1.1:1 to about 1.3:1.In one aspect, this mol ratio is about 1.2:1.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step C, alkali is triethylamine.In one aspect, the mol ratio of triethylamine and formula 4A compound is about 1:1 to about 2:1.In yet another aspect, this mol ratio is about 1.1:1 to about 1.7:1.In yet another aspect, this mol ratio is about 1.3:1.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step C, react and carry out in polar aprotic solvent.In one aspect, polar aprotic solvent is tetrahydrofuran (THF).
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step C, the temperature of reacting at about-10 DEG C to about 10 DEG C is carried out.In one aspect, temperature is about-5 DEG C to about 5 DEG C.In yet another aspect, temperature is about 0 DEG C.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step C, during aftertreatment, reaction mixture H
2o quencher, then uses acidifying.In one aspect, acid is HCl.
the method of scheme 2
In one aspect, the present invention relates to the compound of preparation formula I
Or the method for its pharmacy acceptable salt or solvate, wherein
Represent that substituting group is in α or β stereochemistry at the dotted line key of the 7th (----);
R is hydrogen or hydroxyl; And
R
1for hydrogen or C
1-C
6alkyl,
Said method comprising the steps of:
Step 1: make the converting compounds of formula II become the compound of formula III:
;
Step 2: the compound making the converting compounds accepted way of doing sth IV of formula III:
;
Step 3: the compound making the converting compounds accepted way of doing sth V of formula IV:
;
Step 4: the compound making the converting compounds accepted way of doing sth VI of formula V:
;
Step 5: the compound making the converting compounds accepted way of doing sth VII of formula VI:
; With
Step 6: the compound making the converting compounds accepted way of doing sth I-Na of formula VII:
。
In one aspect, the present invention relates to the compound of preparation formula I or the method for pharmacy acceptable salt, wherein R is hydroxyl.In yet another aspect, R is hydrogen.In one aspect, R
1for C
1-C
6alkyl.In one aspect, R
1for methyl.In yet another aspect, R
1for ethyl.In yet another aspect, R
1for propyl group.In yet another aspect, R is hydrogen, and R
1for C
1-C
6alkyl.In yet another aspect, R is hydroxyl, and R
1for C
1-C
6alkyl.In yet another aspect, R is hydrogen, and R
1for C
1-C
3alkyl.In yet another aspect, R is hydroxyl, and R
1for C
1-C
3alkyl.
In one aspect, the present invention relates to the compound of preparation formula I or the method for its pharmacy acceptable salt or solvate, wherein said salt is selected from
。
In one aspect, the present invention relates to the compound of preparation formula I or the method for its pharmacy acceptable salt or solvate, wherein said salt is selected from
。
step 4
In one aspect, the present invention relates to the compound of preparation formula I
Or its pharmacy acceptable salt (such as, formula IA, IB, IC, ID, IAA, IBB, ICC and IDD any one) or the method for solvate, wherein
Represent that substituting group is in α or β stereochemistry at the dotted line key of the 7th (----);
R is hydrogen or hydroxyl; And
R
1for hydrogen or C
1-C
6alkyl,
Said method comprising the steps of:
Step 4: the compound making the converting compounds accepted way of doing sth VI of formula V:
。
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 4, make compound and the RuCl of formula V
3, NaIO
4and acid-respons, with the compound of production VI.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 4, the compound of formula V and RuCl
3mol ratio be about 18:1 to about 22:1.In one aspect, this mol ratio is about 19:1 to about 21:1.In yet another aspect, this mol ratio is about 20:1.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 4, acid is H
2sO
4, HCl, HClO
4or HIO
4.In one aspect, acid is 2NH
2sO
4.In yet another aspect, acid is 2NHCl.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 4, compound and the mol ratio of acid of formula V are about 2:1 to about 6:1.In one aspect, this mol ratio is about 5:1 to about 3:1.In yet another aspect, this mol ratio is about 4:1.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 4, react and carry out in the mixture of solvent.In one aspect, the mixture of solvent comprises a kind of polar aprotic solvent and two kinds of polar aprotic solvents.In one aspect, polar aprotic solvent is H
2o.In one aspect, polar aprotic solvent is acetonitrile and ethyl acetate.In one aspect, polar aprotic solvent is acetonitrile and chloroform.In one aspect, the mixture of solvent is H
2o/ ethylacetate/acetonitrile or H
2o/ chloroform/acetonitrile.
In one aspect, H
2o: ethyl acetate: the ratio of acetonitrile is that about 1:1:1 is to about 1:3:2 volume ratio.In yet another aspect, this is than being about 1:1.5:1 extremely about 1:2.5:1.5 volume ratio.In yet another aspect, this is than being about 1:2:1.5 volume ratio.
In one aspect, the mixture of solvent comprises a kind of polar aprotic solvent and a kind of polar aprotic solvent.In yet another aspect, polar aprotic solvent is H
2o.In one aspect, polar aprotic solvent is chloroform, acetonitrile or acetone.In one aspect, the mixture of solvent is H
2o/ chloroform, H
2o/ acetonitrile or H
2o/ acetone.
In one aspect, the mixture of solvent comprises two kinds of polar aprotic solvents.In one aspect, polar aprotic solvent is H
2o and the trimethyl carbinol.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 4, the temperature of reacting at about-10 DEG C to about 10 DEG C is carried out.In yet another aspect, temperature is about-5 DEG C to about 5 DEG C.In yet another aspect, temperature is about 0 DEG C.
step 4X
In one aspect of the invention, the step 4 in step 4X alternative scheme 2.In one aspect, the present invention relates to the compound of preparation formula I
Or its pharmacy acceptable salt (such as, formula IA, IB, IC, ID, IAA, IBB, ICC and IDD any one) or the method for solvate, wherein
Represent that substituting group is in α or β stereochemistry at the dotted line key of the 7th (----);
R is hydrogen or hydroxyl; And
R
1for hydrogen or C
1-C
6alkyl,
Said method comprising the steps of:
Step 4X: the compound making the converting compounds accepted way of doing sth VII of formula V:
。
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 4X, make compound and the O of formula V
3solid/liquid/gas reactions, with the compound of production VII.In one aspect, O
3gas also comprises O
2gas.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 4X, make gas pass through reaction mixture with about 4psi to about 15psi bubbling.In one aspect, gas passes through reaction mixture with about 10psi to about 15psi bubbling.In yet another aspect, gas passes through reaction mixture with about 12psi bubbling.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 4X, react and carry out in polar aprotic solvent.In one aspect, polar aprotic solvent is methylene dichloride.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 4X, the temperature of reacting at about-73 DEG C to about-78 DEG C is carried out.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, described method is included in step 4X the compound and NaBH that make formula V further
4react in an inert atmosphere.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, the compound of its Chinese style V and NaBH
4mol ratio be about 1:2 to about 1:4.In one aspect, the compound of formula V and NaBH
4mol ratio be about 1:3.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, described method is included in step 4X further and adds polar aprotic solvent to reaction mixture.In one aspect, polar aprotic solvent is selected from methyl alcohol and ethanol.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein inert atmosphere is nitrogen atmosphere.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 4X, during aftertreatment, acid is added to reaction mixture.In one aspect, acid is HCl.
step 6
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, said method comprising the steps of:
Step 4: the compound making the converting compounds accepted way of doing sth VI of formula V:
; With
Step 6: the salt making the converting compounds accepted way of doing sth I-Na of formula VII:
。
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 6, the compound of formula VII and sulphonating agent are reacted, with the salt of production I-Na.In one aspect, sulphonating agent is sulphur trioxide, chlorsulfonic acid or thionamic acid.In one aspect, sulphonating agent is sulfur trioxide complex.In one aspect, sulfur trioxide complex is selected from sulfur trioxide pyridine, sulphur trioxide dioxane and sulfur trioxide trimethylamine.In one aspect, sulfur trioxide complex is sulfur trioxide pyridine.
In one aspect, the mol ratio of sulphonating agent and formula VII compound is about 2:1 to about 1:1.In yet another aspect, this mol ratio is about 1.5:1 to about 1.2:1.In yet another aspect, this mol ratio is about 1.4:1.In yet another aspect, this mol ratio is about 1.35:1.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 6, react and carry out in polar aprotic solvent.In one aspect, polar aprotic solvent is pyridine.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 6, the temperature of reacting at about 10 DEG C to about 30 DEG C is carried out.In yet another aspect, temperature is about 15 DEG C to about 25 DEG C.In yet another aspect, temperature is about 20 DEG C to about 23 DEG C.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 6, reaction under an inert atmosphere.In yet another aspect, inert atmosphere is nitrogen atmosphere.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in step 6, during aftertreatment, carry out the resistates of reaction mixture with alkali and polar aprotic solvent process.In one aspect, polar aprotic solvent is C
1-C
6alcohol.In one aspect, polar aprotic solvent is C
1-C
3alcohol.In one aspect, polar aprotic solvent is CH
3oH.In one aspect, alkali is NaOH.In one aspect, alkali is CH
310% (w/w) solution of NaOH in OH.
step 5
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, said method comprising the steps of:
Step 4: the compound making the converting compounds accepted way of doing sth VI of formula V:
,
Step 5: the compound making the converting compounds accepted way of doing sth VII of formula VI:
, and
Step 6: the salt making the converting compounds accepted way of doing sth I-Na of formula VII:
。
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in steps of 5, the compound of formula VI and reductive agent are reacted, with the compound of production VII.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, described method comprises further makes the compound of formula VI and a kind of reaction reaction, in steps of 5 with the acid anhydride of the compound of production VI.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, described method comprises the compound and chloro-formic ester reagent and alkali reaction that make formula VI in steps of 5 further, with the acid anhydride of the compound of production VI.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, described method comprises further makes the acid anhydride of the compound of formula VI and a kind of reaction reaction, in steps of 5 with the compound of production VII.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, described method comprises acid anhydride and the hydride reaction of the compound making formula VI in steps of 5 further, with the compound of production VII.
In one aspect, the hydroxyl of the 7th of formula VII compound is in α position.In yet another aspect, the hydroxyl of the 7th of formula VII compound is in β position.
In one aspect, hydride is NaBH
4, Na/t-BuOH, LiAlH
4, NaAlH
2(OC
2h
4oCH
3)
2or LiBH
4.In yet another aspect, hydride is NaBH
4.In one aspect, NaBH
4be about 8:1 to about 12:1 with the mol ratio of formula VI compound.In yet another aspect, this mol ratio is about 9:1 to about 11:1.In yet another aspect, this mol ratio is about 10:1.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in steps of 5, chloro-formic ester reagent is isobutyl chlorocarbonate, Vinyl chloroformate, isopropyl chlorocarbonate or isobutylchloroformate.In one aspect, chloro-formic ester reagent is isobutyl chlorocarbonate.
In one aspect, the mol ratio of isobutyl chlorocarbonate and formula VI compound is about 1:1 to about 1.5:1.In one aspect, this mol ratio is about 1.1:1 to about 1.3:1.In one aspect, this mol ratio is about 1.2:1.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in steps of 5, alkali is triethylamine.In one aspect, the mol ratio of triethylamine and formula VI compound is about 1:1 to about 2:1.In yet another aspect, mol ratio is about 1.3:1 to about 1.7:1.In yet another aspect, this mol ratio is about 1.5:1.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in steps of 5, react and carry out in polar aprotic solvent.In one aspect, polar aprotic solvent is tetrahydrofuran (THF).
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in steps of 5, the temperature of reacting at about-10 DEG C to about 10 DEG C is carried out.In one aspect, temperature is about-5 DEG C to about 5 DEG C.In yet another aspect, temperature is about 0 DEG C.
In one aspect, the present invention relates to preparation formula I, the compound of IA, IB, IC, ID, IAA, IBB, ICC or IDD or the method for pharmacy acceptable salt, wherein in steps of 5, during aftertreatment, reaction mixture H
2o quencher, then uses acidifying.In one aspect, acid is HCl.
definition
For simplicity, some term used in this concentrated specification sheets, embodiment and accessory claim.
For avoiding doubt, term " compound of the present invention " refers to compound disclosed herein, and such as, compound of the present invention comprises the compound of formula I, IA, IB, IC, ID, IAA, IBB, ICC and IDD.Should be appreciated that, as long as use this term in the context of the present invention, just relate to free alkali and corresponding pharmacy acceptable salt and solvate simultaneously, its condition is them to be possible at ambient and/or to be suitable.
Term used herein " pharmaceutically acceptable " refers within the scope of reliable medical judgment, be applicable to using and there is no undue toxicity, stimulation, anaphylaxis or other problem or complication with the contact tissue of humans and animals, the compound, material, composition, carrier and/or the formulation that match with rational income/Hazard ratio.
" pharmacy acceptable salt " of term compound used herein refers to pharmaceutically acceptable and has the salt of the required pharmacologically active of parent compound.
Term used herein " method of the present invention " refers to the method by preparation described herein compound of the present invention, and wherein the method comprises any one or more steps described in scheme 1 or scheme 2.
All terms " mol ratio " refer to the ratio of the molar equivalent of X and the molar equivalent of Y herein, and wherein X and Y can be the reagent in such as reaction mixture.
(such as, C when having an index number scope after atom or chemical part
1-6), the present invention is intended to comprise each numerical value in this scope and all intermediate ranges.Such as, " C
1-6alkyl " be intended to comprise have 1,2,3,4,5,6, the alkyl of 1-6,1-5,1-4,1-3,1-2,2-6,2-5,2-4,2-3,3-6,3-5,3-4,4-6,4-5 and 5-6 carbon." alkyl " used herein or " C
1, C
2, C
3, C
4, C
5or C
6alkyl " be intended to comprise C
1, C
2, C
3, C
4, C
5or C
6straight chain (linearly) radical of saturated aliphatic alkyl and C
3, C
4, C
5or C
6side chain radical of saturated aliphatic alkyl.Such as, C
1-6alkyl is intended to comprise C
1, C
2, C
3, C
4, C
5and C
6alkyl.The example of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, sec.-amyl sec-pentyl secondary amyl and n-hexyl.
Term used herein " Ac " refers to ethanoyl.
Term used herein " THF " refers to tetrahydrofuran (THF).
Term used herein " DCM " refers to methylene dichloride or methylene chloride.
Term used herein " EtOAc " refers to ethyl acetate.
Term used herein " TLC " refers to thin-layer chromatography.
Term used herein " dotted line key (----) " refers to two kinds of possible positions of the substituent point connected at dotted line key.Such as, when being in α stereochemistry for the 7th of formula I, structure is as follows:
(I-α)。
When being in β stereochemistry for the 7th of formula I, structure is as follows:
(I-β)。
Therefore, should be appreciated that, except as otherwise noted, otherwise include within the scope of the invention from the isomer (such as, all enantiomers and diastereomer) that unsymmetrical carbon produces.Synthesize by conventional separation techniques with by zinc bromide, these isomer can be obtained in a substantially pure form.In addition, the structure discussed in this application also comprises its tautomers all with other compound and part.Compound of the present invention and synthetic intermediate can exist by stereoisomer form, therefore, can be used as independent steric isomer or prepare as mixture.
Term used herein " acid anhydride of formula VI compound " refers to the compound with following structure:
Wherein R
2for C
1-C
6alkyl or benzyl.
The present invention also comprises isotope-labeled compound of the present invention, identical with described in formula I, IA, IB, IC, ID, IAA, IBB, ICC and IDD of these compounds, but one or more atom is replaced by the atomic mass of atomic mass or mass number and usual natural discovery or the different atom of mass number.The isotopic example that can be incorporated into the compounds of this invention comprises the isotropic substance of hydrogen, carbon, nitrogen, fluorine, such as
3h,
11c and
14c.
Usually, replacing nonisotopic labels reagent with the facile isotopic labeling reagent of appearance, by carrying out step disclosed in the solution of the present invention and/or embodiment, isotope-labeled compound of the present invention can be prepared.In one aspect, compound of the present invention is without isotopic labeling.
" solvate " refers to the solvent addition forms comprising stoichiometry or non-stoichiometric solvent.Compound of the present invention can have and retains fixed molar ratio solvent molecule in crystalline solid state, thus forms the tendency of solvate.If solvent is water, then the solvate generated is hydrate, and when solvent is alcohol, the solvate of generation is alcoholate.By one or more water molecules with wherein water as H
2o keeps a kind of material chemical combination of its molecular state, and generate hydrate, this chemical combination can generate one or more hydrate.In addition, compound of the present invention, such as, the salt of compound, can aquation or nonhydratable (anhydrous) form or exist as the form of the solvate with other solvent molecule.The unrestricted example of hydrate comprises mono-hydrate, dihydrate etc.The unrestricted example of solvate comprises alcohol solvent compound, acetone solvate etc.
" tautomer " refers to its structure significantly different but compound that is that exist in easily and fast balance in atomic arrangement.Should be appreciated that, compound of the present invention can be depicted as different tautomers.Should also be clear that when compound of the present invention and synthetic intermediate of the present invention have tautomeric form, within the scope of the invention, and any tautomeric forms is not got rid of in the name of the compounds of this invention to the equal purport of all tautomeric forms.Compound of the present invention and synthetic intermediate of the present invention can several tautomeric forms exist, and comprise keto-enol.Such as, in keto-enol tautomerism, transfer while there is electronics and hydrogen atom.Tautomer exists as the mixture of tautomerism group in the solution.In solid form, usual a kind of tautomer is preponderated.Even if a kind of tautomer may be described, but the present invention includes all tautomers of the compounds of this invention.
Now describe the present invention by written explanation, but those skilled in the art will appreciate that and can implement the present invention in different embodiments, and description and following examples were for illustrative purposes in the past, instead of the restriction to claims.
In this manual, unless the context clearly indicates otherwise, otherwise singulative also comprises plural form.Unless otherwise defined, otherwise all technology used herein and scientific terminology all have the identical meanings that those skilled in the art generally understand.If clashed, should be as the criterion with this specification sheets.
Except as otherwise noted, otherwise all per-cent used herein and ratio all by weight.
Embodiment
In one embodiment of the invention, fusing point Buchi535 electric heating device measures, and does not correct.NMR spectrum BrukerAC200MHz or 400MHZ spectrograph obtain, and chemical shift is with PPM (ppm) report.Abbreviation used is as follows: s, unimodal; Bs, wide unimodal; D, doublet; Dd, double doublet; M, multiplet.Flash column chromatography Merck silica gel 60 (0.040-0.063mm) carries out, and indicates use BiotageSP1HPCF separation module.Use 25+M (25mmx15.0cm, 40g) cylinder.TLC carries out on the precoating TLC plate with silica gel 60F-254 (Merck).By with phosphomolybdate reagent (5% solution, in EtOH) colour developing and warm, observe spot.
embodiment 1-prepares 3 α, and-5 β-cholane-23-falls in 7 α, 23-trihydroxy--6 α-ethyl-24-
o-sodium sulfate salt
step 1a: prepare 3 α, 7 alpha-dihydroxy--6 α-ethyl-5 β-ursodeoxycholic acid methyl esters (IIIA)
By tosic acid mono-hydrate (4g, 21.03mmol) join IIA (40g in methyl alcohol (500mL), stirred solution 95.1mmol), supersound process reaction mixture, until raw material II A completely dissolve (being checked by TLC), this needs about 3h.Make solvent vaporising under vacuum, the resistates containing IIIA obtained is dissolved in methylene dichloride (500mL), and washs with saturated sodium bicarbonate aqueous solution (3x100mL), water (100mL) and salt solution (100mL).Containing the organic layer of IIIA through anhydrous sodium sulfate drying, then vaporising under vacuum solvent.
step 2a: prepare 3 α-acetoxyl group-7 Alpha-hydroxy-6 α-ethyl-5 β-bisnorchola alkyl diphenyl base ethene (IVA)
Make 3 α, 7 alpha-dihydroxy--6 α-ethyl-5 β-ursodeoxycholic acid methyl esters (IIIA) is dissolved in the THF (300mL) of new distillation, and gained mixture is warmed to 50 DEG C under nitrogen atmosphere, stirs simultaneously.Then drip the 1M phenyl-magnesium-bromide in THF (800mL), gained reaction mixture is stirred at uniform temp and spends the night.Make reaction mixture be cooled to room temperature, and add hexanaphthene (25mL).Reaction mixture is filtered, makes glue-solid residue be dissolved in the mixture (carefully) of 3N hydrochloric acid soln (800mL) and DCM (200mL).Stir gained mixture 30 minutes.Be separated the organic phase containing IVA, aqueous phase DCM (2x200mL) extracts.With the merging organic layer of salt water washing containing IVA, through Na
2sO
4drying, and vaporising under vacuum solvent.Thick resistates containing IVA is dissolved in DCM (500mL), with saturated sodium bicarbonate solution (2x100mL), water (100mL), salt solution (100mL) washing, through anhydrous sodium sulfate drying, and concentrates in a vacuum.By gained resistates (containing IVA) for next step, without the need to being further purified.
step 3a: prepare 3 α-acetoxyl group-7 Alpha-hydroxy-6 α-ethyl-5 β-bisnorchola alkyl diphenyl base ethene (VA)
By diacetyl oxide (9.92mL, 105.14mmol), pyridine (1.6mL, 19.78mmol) and 4-dimethylaminopyridine (0.8g.6.55mmol) join and newly distill 3 α in THF (300mL), the stirred solution of 7 alpha-dihydroxy--6 α-ethyl-5 β-bisnorchola alkyl diphenyl base ethene (IVA) (95.1mmol).Reaction mixture is kept to spend the night in room temperature.With water (100ml) diluted reaction mixture, and extract with DCM (3x150mL).The organic layer washed with brine merged, through anhydrous sodium sulfate drying, and makes solvent evaporate.Resistates containing VA is used for next step, without the need to being further purified.
1H-NMR(CDCl
3)δ0.66(3H,s,C
H 3-18);0.77(3H,s,C
H 3-26);1.00(3H,d,C
H 3-21);1.20(3H,s,C
H 3-19);1.96(3H,s,AcO),2.18-2.31(1H,m,C
H-22);3.70(1H,m,C
H-7);4.55(1H,m,C
H-3);6.11(1H,dd,
J 1=6.2Hz,
J 2=8.3Hz;C
H-23);7.14-7.36(10H,m,Ph)。
step 4a: prepare 3 α-acetoxyl group-6 α-ethyl-7-ketone-24-and fall-5 β-cholane-23-acid (VIA)
At the H of 13mL
2o and 2NH
2sO
4(1.7mL) NaIO is stirred in
4(13.2g, 61.86mmol).After 15 minutes, make gained reaction mixture be cooled to 0 DEG C, and add RuCl
3(71.3mg, 0.34mmol).Stirred reaction mixture, until color becomes glassy yellow.Add ethyl acetate (27mL) and acetonitrile (20mL), and stir gained reaction mixture 5 minutes.VA (4g, 6.87mmol) is joined the reaction mixture of 0 DEG C, and stir, until exhaust all VA (being checked by TLC).Reaction mixture is filtered, pours H into
2o, and extract by ethyl acetate (3x100mL).Use saturated Na
2s
2o
3solution washing contains the merging organic layer of VIA, through anhydrous Na
2sO
4drying, and concentrate under vacuo.Gained resistates, by purification by flash chromatography, obtains VIA, is the pure solid of white (2.73g, 6.11mmol, 89% productive rate).
1H-NMR(CDCl
3)δ0.71(3H,s,C
H 3-18);0.86-1.07(9H,m,C
H 3-19,C
H 3-21,C-24);2.03(3H,s,AcO);4.48-4.61(1H,m,C
H-3)。
13C-NMR(CDCl
3)δ12.0,12.0,18.8,19.5,21.3,21.8,23.4,24.5,25.9,27.7,28.3,33.4,33.8,35.6,38.8,41.2,42.6,43.6,48.9,49.8,50.4,51.9,54.7,73.2,170.6,179.7,212.6。
step 5a: prepare 3 α-acetoxyl group-7 Alpha-hydroxy-6 α-ethyl-24-and fall-5 β-cholane-23-alcohol (VIIA)
Triethylamine (6.67mL, 3.36mmol) is joined the ice-cooled solution of stirring of VIA (1g, 2.24mmol) and isobutyl chlorocarbonate (3.5mL, 2.67mmol) in THF (20mL).After 1 hour, filter reaction mixture under an argon under vacuo.Process gained solution 1 hour at 0 DEG C with sodium borohydride (847mg, 22.4mmol), sodium borohydride adds in batches.Reaction mixture H
2o (3mL) quencher, in stirring at room temperature other 2 hours, with 3N hydrochloric acid (50mL) acidifying, and extracts by ethyl acetate (3x15mL).The organic extract merged salt solution (1x15mL) washing, through anhydrous Na
2sO
4drying, and concentrate under vacuo.By VIIA (950mg) for next step, without the need to being further purified.
1H-NMR(CDCl
3)δ0.67(3H,s,C
H 3-18);0.86-0.97(9H,m,C
H 3-19,C
H 3-21,C
H 3-24);2.03(3H,s,AcO);3.72(3H,m,(2H,m,C
H-7,C
H 2 -23);4.48-4.61(1H,m,C
H-3)。
13C-NMR(CDCl
3)δ11.6,11.7,18.7,20.7,21.4,22.1,22.9,23.7,26.6,28.4,29.6,32.9,33.2,35.5,38.9,39,.6,40.0,41.1,42.8,45.0,50.5,56.3,60.8,70.7,74.7,170.7。
step 6a: prepare 3 α ,-5 β-cholane-23-falls in 7 α, 23-trihydroxy--6 α-ethyl-24-
o-sodium sulfate salt (IA)
VIIA (8g, 18.4mmol) is joined the suspension of sulfur trioxide pyridine complex (3.95g, 24.84mmol) in anhydrous pyridine (60mL), and in a nitrogen atmosphere room temperature reaction 24 hours.Solvent is evaporated, and gained resistates is dissolved in methyl alcohol (50mL), and by 10% (w/w) solution-treated of NaOH in MeOH (30mL).Reaction mixture refluxed is spent the night.Solvent is evaporated, and gained white solid is dissolved in 30mLH
2o/MeOH solution (1:1, v:v), the Dowex resin activated by NaOH (h=15cm ,=8cm), first uses H
2o (200mL) wash-out, then uses H
2solution (300mL) wash-out of O/MeOH (1:1, v:v).The flow point comprising IA is evaporated to dry, gained solid, by reversed-phase column RP-18 (LobarC) purifying, uses H
2o/MeOH mixture is as moving phase.Obtaining IA (5g, 56% productive rate), is the pure solid of white.
m.p.:183-184℃。
1H-NMR(CD
3OD)δ0.71(3H,s,C
H 3-18);0.89-0.95(6H,m,C
H 3-19,C
H 325);0.99-1.01(3H,d,J=6.5Hz,C
H 3-21);3.31(1H,m,C
H-3);3.65(1H,m,C
H-7);4.0-4.1(2H,m,C
H 2-23)。
13C-NMR(CD
3OD)δ:73.19,71.15,67.20,57.77,51.64,46.95,43.79,43.12,41.54,41.04,36.77,36.62,36.54,34.49,34.41,34.22,31.24,29.34,24.55,23.75,23.48,21.96,19.15,12.19,12.03。
embodiment 2: prepare compound VI IA from VA
Thick VA (672.0g, 1.153mol) is made to be dissolved in methylene dichloride (3.0L).Sample is made to revolve steaming about 2 hours revolving on steaming device (rotavap), until thick VA dissolves completely.Be equipped with that mechanical stirrer, bubbler are external by transferring to containing the solution of VA, thermopair and O
3/ O
2three necks, 12 liters of round-bottomed flasks of inlet tube.Methylene dichloride (2.376L) is added to the solution containing VA.The solution containing VA is made to be cooled to about-73 DEG C to about-78 DEG C.Make O
3/ O
2the mixture (at about 4psi to about 15psi, or at about 12psi) of gas experiences about 2 hours by the stirred solution of VA, until reaction mixture becomes blue/green, TLC proves do not have raw material.By O
3/ O
2gas inlet pipe is closed, and makes N
2about 40 minutes are experienced by reaction mixture.Xiang Yue-50 DEG C has N to about-75 DEG C
2the reaction mixture passed through adds NaBH
4(131.0g, 3.457mol) and EtOH (1.4L).By reaction mixture about-50 DEG C to about-55 DEG C stir abouts 20 minutes, at this moment, reaction mixture is made to be warmed to room temperature, then at N
2lower stirring is spent the night.Carry out TLC proved response complete.
Reaction mixture was cooled to through about 1 hour about-5 DEG C to about-10 DEG C (or to about-6 DEG C).HCl (1N, 3.1L) is slowly added to reaction mixture through about 2 hours.The pH of gained reaction mixture is about 3.Make reaction mixture be warmed to room temperature through about 1 hour, then add EtOAc (6.5L).Abundant stirring gained mixture.Organic layer is separated with waterbearing stratum.Waterbearing stratum is extracted with EtOAc.Merge the organic layer containing VIIA, with water (5.5L), salt solution (2 times, each 1.3L) washing, then through Na
2sO
4dry.Filter organic layer, gained solution is concentrated into dry, obtains the thick VIIA of 666.0g.
Compound VI I can according to the following stated step purifying.The above compound VI IA obtained is made to be dissolved in methylene dichloride (2.0L rinses with 0.6L).Biotage post is rinsed with THF (3 times, each 20L).Biotage post is proved clean by TLC.Biotage column equilibration is made with hexane (20L).VIIA in methylene dichloride is poured on post.First post uses 100L hexane: EtOAc (9:1) wash-out, then uses 200L hexane: EtOAc (8.5:1.5) wash-out, then uses 100L hexane: EtOAc (7:3) wash-out.Make the flow point containing purifying VIIA be concentrated into dry, obtain 255.0g (50.9% productive rate, from VA).
Again according to the compound VI IA of following steps purifying from the first purifying.Biotage post is rinsed, until TLC proves clean with THF.Make compound VI IA (241.5g) be dissolved in methylene dichloride (0.480L rinses with 0.480L), and be poured on post.Post 50L hexane: EtOAc (9:1) wash-out, uses 50L hexane: EtOAc (8.5:1.5) wash-out, uses 100L hexane: EtOAc (8:2) wash-out, then use 200L hexane: EtOAc (7:3) wash-out.Make the flow point containing pure VIIA be concentrated into dry, obtain 169.0g.For the HPLC color atlas of purifying VIIA, see Fig. 1, for purifying VIIA's
1hNMR composes, and sees Fig. 2.
embodiment 3: prepare 3 α ,-5 β-cholane-23-falls in 7 α, 23-trihydroxy--6 α-ethyl-24-
o-sodium sulfate salt
steps A a:3 α, 7 α-diacetoxy-6 α-ethyl-5 β-bisnorchola alkyl diphenyl base ethene (3)
Make the solution reaction of compound 2 (1g, 2.4mmol) and AmberlistA-15 in methyl alcohol (20mL), until raw material completely dissolve (being checked by TLC) (4h).Filter reaction mixture, wash A-15 with MeOH, and under vacuo except desolventizing.Make the methyl esters (1.1g) so generated be dissolved in the THF (15mL) of new distillation, mixture stirs at magnetic and is warmed to 50 DEG C under nitrogen atmosphere.Then Et is dripped
23M phenyl-magnesium-bromide in O (3.83mL, 12mmol), stirs other 4h by gained mixture at uniform temp.Make solution be cooled to room temperature, and add hexanaphthene (25mL).Filter gained suspension, make glue-solid residue be dissolved in the mixture of 3N hydrochloric acid soln (50mL) and methylene dichloride (25mL).Stir the mixture 30 minutes.Be separated organic phase, aqueous phase methylene dichloride (3x25mL) extracts.The organic layer washed with brine merged, through Na
2sO
4drying is also concentrated.Crude product mixture is made to be dissolved in methylene dichloride (30mL) again, and at Bi (OTf)
3(15mg, 0.115mmol) reacts 3 hours in room temperature and diacetyl oxide (0.72mL, 7.6mmol) under existing.Filtering mixt on Celite, with the NaOH1M process in water (50mL), and extracts with methylene dichloride (3x15mL).The organic layer washed with brine merged, through anhydrous sodium sulfate drying, and concentrated.After silicagel pad is filtered, obtaining compound 3 with 92% productive rate (1.15g), is white solid.
1H-NMR(CDCl
3)δ0.64(3H,s,C
H 3-18);0.88(3H,t,C
H 3-26);0.93(3H,s,C
H 3-19);1.01(3H,d,C
H 3-21);2.03(3H,s,AcO),2.06(3H,s,AcO),2.18-2.31(1H,m,C
H-22);4.58(1H,m,C
H-3);5.09(1H,m,C
H-7);6.11(1H,dd,
J 1=6.2Hz,
J 2=8.3Hz;C
H-23);6.75-7.37(10H,m,Ph).
13C-NMR(CDCl
3)δ11.3,11.4,18.7,20.3,21.0,21.2,21.9,22.7,23.6,26.4,27.8,28.6,33.8,34.8,35.1,35.6,36.6,38.5,39.0,41.0,42.6,44.6,50.2,55.5,72.8,74.2,126.4,126.7,127.8,128.6,129.6,140.1,141.9,142.6,170.1,170.3。
-5 β-cholane-23-acid (4) falls in step Ba:3 α, 7 α-diacetoxy-6 α-ethyl-24-
At the H of 1.3mL
2o and 2NH
2sO
4(0.17mL) NaIO is stirred in
4(1.32g, 6.186mmol).After 15 minutes, make solution be cooled to 0 DEG C, and add RuCl
3(7.13mg, 0.034mmol).Stir this mixture, until color becomes glassy yellow.Add ethyl acetate (2.7mL) and acetonitrile (2.0mL), and stir gained mixture 5 minutes.Add compound 3 (400mg, 0.687mmol) at 0 DEG C, and stir the mixture, until exhaust compound 2 raw material.Mixture is leached, pours into H
2on O, and extract by ethyl acetate (3x25mL).The saturated Na of organic layer merged
2s
2o
3solution washing, through Na
2sO
4drying, and under reduced pressure concentrate.Gained resistates, by purification by flash chromatography, obtains compound 4 (2.7g, 6.1mmol, 89% productive rate).
1H-NMR(CDCl
3)δ0.70(3H,s,C
H 3-18);0.88(3H,t,C
H 3-26);0.96(3H,s,C
H 3-19);1.04(3H,d,C
H 3-21);2.06(3H,s,AcO),2.09(3H,s,AcO),2.47(1H,dd,C
H-22);4.54-4.62(1H,m,C
H-3);5.12(1H,s,C
H-7).
13C-NMR(CDCl
3)δ11.2,11.3,19.1,20.2,21.1,21.8,22.6,23.4,27.7,28.6,33.6,34.0,35.5,38.9,40.0,41.1,43.0,45.0,50.6,55.7,73.1,74.6,170.5,170.7,177.9。
-5 β-cholane-23-alcohol (5) falls in step C:3 α, 7 α-diacetoxy-6 α-ethyl-24-
The stirring ice cold solution newly distilling compound 4 (300mg, 0.6mmol), isobutyl chlorocarbonate (0.72mmol) and triethylamine (0.78mmol) in THF (20mL) is made to react 1 hour.Then in argon atmospher, reaction mixture is filtered under vacuo.Make thick material be cooled to 0 DEG C, and add sodium borohydride (1.27g, 33.6mmol) in batches.Gained mixture is stirred 1 hour, then adds H
2o (3mL).At stirring at room temperature reaction mixture other 2 hours, then use 3N hydrochloric acid (50mL) acidifying, and extract by ethyl acetate (3x15mL).With the organic extract that salt solution (1x15mL) washing merges, through Na
2sO
4drying, and under reduced pressure concentrate, obtain compound 5 (300mg), this compound is used for next step, without the need to being further purified.
1H-NMR(CDCl
3)δ0.63(3H,s,C
H 3-18);0.86-0.97(9H,m,C
H 3-19,C
H 3-21,C
H 3-25);2.00(3H,s,AcO);2.00(3H,s,AcO);3.57-3.83(2H,m,C
H 2 -23);4.54-4.62(1H,m,C
H-3);5.12(1H,s,C
H-7).
13C-NMR(CDCl
3)δ11.6,11.7,18.8,20.7,21.3,21.4,5,22.2,23.0,23.8,26.8,28.2,29.0,32.9,34.1,35.1,35.5,38.9,39.4,41.1,42.9,45.0,50.5,56.3,60.8,73.2,74.5,170.4,170.6。
step D:3 α ,-5 β-cholane-23-falls in 7 α, 23-trihydroxy--6 α-ethyl-24-
o-sodium sulfate salt (IA)
Compound 5 is joined the suspension of sulfur trioxide pyridine complex (190mg, 1.2mmol) in anhydrous pyridine (2mL), and stir gained mixture 24 hours in a nitrogen atmosphere.Except desolventizing, resistates is made to be dissolved in methyl alcohol (5mL), and with 10% (w/w) solution at reflux overnight of NaOH in MeOH (7mL).Solvent is evaporated, and gained white solid is dissolved in 5mLH
2o/MeOH (1:1, v:v) solution, the Dowex resin activated by NaOH, first uses H
2o (40mL) wash-out, then uses H
2o/MeOH (1:1, v:v) (300mL) wash-out.The flow point of inclusion compound is evaporated to dry, gained solid, by reversed-phase column RP-18 (LobarC) purifying, uses H
2the solution of O/MeOH is as moving phase.Compound I A is obtained with 55% productive rate.
m.p.:183-184℃。
1H-NMR(CD
3OD)δ0.71(3H,s,C
H 3-18);0.89-0.95(6H,m,C
H 3-19,C
H 3-25);0.99-1.01(3H,d,J=6.5Hz,C
H 3-21);3.31(1H,m,C
H-3);3.65(1H,m,C
H-7);4.0-4.1(2H,m,C
H 2-23).
13C-NMR(CD
3OD)δ:73.19,71.15,67.20,57.77,51.64,46.95,43.79,43.12,41.54,41.04,36.77,36.62,36.54,34.49,34.41,34.22,31.24,29.34,24.55,23.75,23.48,21.96,19.15,12.19,12.03。
equivalent
Person of skill in the art will appreciate that, or only just can determine with routine test, many equivalents of specific embodiments as herein described and method.Such equivalent is intended to comprise within the scope of the invention.
The all patents quoted in this article, patent application and bibliographic reference are clearly incorporated herein by reference.
Claims (21)
1. the compound of a preparation formula I
Or the method for its pharmacy acceptable salt or solvate, wherein
Represent that substituting group is in α or β stereochemistry at the dotted line key of the 7th (----);
R is hydrogen or hydroxyl; And
R
1for hydrogen or C
1-C
6alkyl;
Said method comprising the steps of:
Step B: the compound making the converting compounds accepted way of doing sth 4A of formula 3A:
Wherein step B comprises the compound and RuCl that make formula 3A
3, NaIO
4and acid-respons, with the compound of production 4A.
2. the process of claim 1 wherein R
1for ethyl.
3. the process of claim 1 wherein that described compound is selected from
。
4. the process of claim 1 wherein that step B comprises the compound and NaIO making formula 3A
4reaction.
5. the method for claim 1, described method is further comprising the steps:
Step D: the compound making the converting compounds accepted way of doing sth I-Na of formula 5A:
。
6. the method for claim 5, wherein step D comprises the compound that makes formula 5A and sulphonating agent reacts, with the compound of production I-Na.
7. the method for claim 5, described method is further comprising the steps:
Step C: the compound making the converting compounds accepted way of doing sth 5A of formula 4A:
。
8. the method for claim 7, wherein step C comprises the compound that makes formula 4A and reductive agent reacts, with the compound of production 5A.
9. the method for claim 7, described method is further comprising the steps:
Steps A: the compound making the converting compounds accepted way of doing sth 3A of formula II:
。
10. the compound of a preparation formula I
Or the method for its pharmacy acceptable salt or solvate, wherein
Represent that substituting group is in α or β stereochemistry at the dotted line key of the 7th (----);
R is hydrogen or hydroxyl; And
R
1for hydrogen or C
1-C
6alkyl,
Said method comprising the steps of:
Step 4: the compound making the converting compounds accepted way of doing sth VI of formula V:
,
Wherein step 4 comprises the compound and RuCl that make formula V
3, NaIO
4and acid-respons, with the compound of production VI.
The method of 11. claims 10, wherein R
1for ethyl.
The method of 12. claims 10, wherein said compound is selected from
。
The method of 13. claims 10, wherein step 4 comprises the compound and NaIO that make formula V
4reaction.
The method of 14. claims 10, described method is further comprising the steps:
Step 6: the compound making the converting compounds accepted way of doing sth I-Na of formula VII:
。
The method of 15. claims 14, wherein step 6 comprises the compound that makes formula VII and sulphonating agent reacts, with the salt of production I-Na.
The method of 16. claims 14, described method is further comprising the steps:
Step 5: the compound making the converting compounds accepted way of doing sth VII of formula VI
。
The method of 17. claims 16, wherein step 5 comprises the compound that makes formula VI and reductive agent reacts, with the compound of production VII.
The method of 18. claims 16, described method is further comprising the steps:
Step 1: make the converting compounds of formula II become the compound of formula III:
;
Step 2: the compound making the converting compounds accepted way of doing sth IV of formula III:
; With
Step 3: the compound making the converting compounds accepted way of doing sth V of formula IV:
。
The compound of 19. 1 kinds of preparation formula I
Or the method for its pharmacy acceptable salt or solvate, wherein
Represent that substituting group is in α or β stereochemistry at the dotted line key of the 7th (----);
R is hydrogen or hydroxyl; And
R
1for hydrogen or C
1-C
6alkyl,
Said method comprising the steps of:
Step BX: the compound making the converting compounds accepted way of doing sth 4A of formula 3A:
,
Wherein step BX comprises the compound and O that make formula 3A
3solid/liquid/gas reactions, with the compound of production 4A.
The compound of 20. 1 kinds of preparation formula I
Or the method for its pharmacy acceptable salt or solvate, wherein
Represent that substituting group is in α or β stereochemistry at the dotted line key of the 7th (----);
R is hydrogen or hydroxyl; And
R
1for hydrogen or C
1-C
6alkyl,
Said method comprising the steps of:
Step 4X: the compound making the converting compounds accepted way of doing sth VII of formula V:
,
Wherein step 4X comprises the compound and O that make formula V
3solid/liquid/gas reactions, with the compound of production VII.
21. 1 kinds of compounds, described compound has following structure:
。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810282054.XA CN108250264A (en) | 2012-10-26 | 2013-10-25 | The method for preparing bile acid derivative |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261718966P | 2012-10-26 | 2012-10-26 | |
US61/718966 | 2012-10-26 | ||
PCT/US2013/066917 WO2014066819A1 (en) | 2012-10-26 | 2013-10-25 | Process for preparing bile acid derivatives |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810282054.XA Division CN108250264A (en) | 2012-10-26 | 2013-10-25 | The method for preparing bile acid derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105102425A true CN105102425A (en) | 2015-11-25 |
CN105102425B CN105102425B (en) | 2018-04-10 |
Family
ID=50545344
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810282054.XA Pending CN108250264A (en) | 2012-10-26 | 2013-10-25 | The method for preparing bile acid derivative |
CN201380068062.XA Expired - Fee Related CN105102425B (en) | 2012-10-26 | 2013-10-25 | The method for preparing bile acid derivative |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810282054.XA Pending CN108250264A (en) | 2012-10-26 | 2013-10-25 | The method for preparing bile acid derivative |
Country Status (21)
Country | Link |
---|---|
US (2) | US9777038B2 (en) |
EP (1) | EP2912013B1 (en) |
JP (1) | JP6272888B2 (en) |
KR (1) | KR102068381B1 (en) |
CN (2) | CN108250264A (en) |
AU (1) | AU2013334122B2 (en) |
BR (1) | BR112015009395A2 (en) |
CA (1) | CA2889592A1 (en) |
CY (1) | CY1119731T1 (en) |
DK (1) | DK2912013T3 (en) |
ES (1) | ES2655034T3 (en) |
HK (2) | HK1214239A1 (en) |
HU (1) | HUE036887T2 (en) |
IL (1) | IL238454B (en) |
MX (1) | MX361653B (en) |
NO (1) | NO2968302T3 (en) |
NZ (2) | NZ745013A (en) |
PL (1) | PL2912013T3 (en) |
PT (1) | PT2912013T (en) |
SG (1) | SG11201503247UA (en) |
WO (1) | WO2014066819A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109069517A (en) * | 2016-04-19 | 2018-12-21 | 英特塞普特医药品公司 | The method for preparing shellfish cholic acid and its derivative difficult to understand |
WO2019020067A1 (en) * | 2017-07-26 | 2019-01-31 | 正大天晴药业集团股份有限公司 | Method for preparing steroid derivative fxr agonist |
CN109963567A (en) * | 2016-09-30 | 2019-07-02 | 英特塞普特医药品公司 | The crystal form of bile acid derivative |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2912013B1 (en) | 2012-10-26 | 2017-10-11 | Intercept Pharmaceuticals, Inc. | Process for preparing bile acid derivatives |
PL3626725T3 (en) | 2014-05-29 | 2023-04-03 | Bar Pharmaceuticals S.R.L. | Cholane derivatives for use in the treatment and/or prevention of fxr and tgr5/gpbar1 mediated diseases |
EA034739B1 (en) | 2014-11-19 | 2020-03-16 | ЭнЗедПи ЮКей ЛИМИТЕД | 6-alpha.-alkyl-3,7-dione steroids as intermediates for the production of steroidal fxr modulators |
CN107207558B (en) | 2014-11-19 | 2019-10-29 | Nzp英国有限公司 | 6 alpha-alkyl -6,7- diketone the steroids as the intermediate for preparing steroids FXR regulator |
CA2968309A1 (en) | 2014-11-19 | 2016-05-26 | NZP UK Limited | 6-alkyl-7-hydroxy-4-en-3-one steroids as intermediates for the production of steroidal fxr modulators |
TWI686400B (en) | 2014-11-19 | 2020-03-01 | 英商Nzp英國有限公司 | Compounds |
CN104672290B (en) * | 2015-01-05 | 2017-06-06 | 北京普禄德医药科技有限公司 | A kind of medicine of disease for preventing or treating FXR mediations and its production and use |
BR112017016766B1 (en) | 2015-02-06 | 2023-11-07 | Intercept Pharmaceuticals, Inc | COMPOSITION COMPRISING AN FXR AGONIST AND FIBRATE, AS WELL AS USE TO TREAT CHOLESTATIC LIVER DISEASE |
US11072631B2 (en) * | 2015-09-24 | 2021-07-27 | Intercept Pharmaceuticals, Inc. | Methods and intermediates for the preparation bile acid derivatives |
JP6749406B2 (en) | 2015-11-06 | 2020-09-02 | インターセプト ファーマシューティカルズ, インコーポレイテッド | Method for preparing obeticholic acid and its derivatives |
US20200262865A1 (en) * | 2016-02-15 | 2020-08-20 | Alexander Khoruts | Compositions and methods for treating clostridium associated diseases |
JP6968821B2 (en) | 2016-04-13 | 2021-11-17 | インターセプト ファーマシューティカルズ, インコーポレイテッド | How to treat cancer |
GB201608777D0 (en) | 2016-05-18 | 2016-06-29 | Dextra Lab Ltd | Compounds |
GB201608776D0 (en) | 2016-05-18 | 2016-06-29 | Dextra Lab Ltd | Methods and compounds |
WO2019023103A1 (en) | 2017-07-24 | 2019-01-31 | Intercept Pharmaceuticals, Inc. | Isotopically labeled bile acid derivatives |
GB201812382D0 (en) | 2018-07-30 | 2018-09-12 | Nzp Uk Ltd | Compounds |
CN114144185A (en) | 2019-05-30 | 2022-03-04 | 英特塞普特医药品公司 | Pharmaceutical composition comprising an FXR agonist and a fibrate for the treatment of cholestatic liver diseases |
KR20220150270A (en) | 2019-10-07 | 2022-11-10 | 칼리오페, 인크. | GPR119 agonists |
CA3178994A1 (en) | 2020-05-19 | 2021-11-25 | Iyassu Sebhat | Ampk activators |
JP2023531726A (en) | 2020-06-26 | 2023-07-25 | キャリーオペ,インク. | AMPK Activator |
EP4215540A1 (en) | 2020-09-18 | 2023-07-26 | Seoul National University R & DB Foundation | Method for mass-producing sodium taurodeoxycholate |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050080064A1 (en) * | 2001-03-12 | 2005-04-14 | Roberto Pellicciari | Steroids as agonists for fxr |
US20080039435A1 (en) * | 2004-02-26 | 2008-02-14 | Intercept Pharmaceuticals, Inc. | Novel Steroid Agonist For Fxr |
CN101522703A (en) * | 2006-06-27 | 2009-09-02 | 英特塞普特医药品公司 | Bile acid derivatives as fxr ligands for the prevention or treatment of fxr-mediated deseases or conditions |
CN102164940A (en) * | 2008-07-30 | 2011-08-24 | 英特塞普特医药品公司 | TGR5 modulators and methods of use thereof |
CN102282157A (en) * | 2008-11-19 | 2011-12-14 | 英特塞普特医药品公司 | TGR5 Modulators and Methods of Use Thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5216015A (en) | 1991-02-05 | 1993-06-01 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Compounds having hypocholesterolemic properties |
US9943614B2 (en) | 2008-06-17 | 2018-04-17 | Brigham Young University | Cationic steroid antimicrobial diagnostic, detection, screening and imaging methods |
EP2912013B1 (en) | 2012-10-26 | 2017-10-11 | Intercept Pharmaceuticals, Inc. | Process for preparing bile acid derivatives |
-
2013
- 2013-10-25 EP EP13849263.2A patent/EP2912013B1/en active Active
- 2013-10-25 MX MX2015005286A patent/MX361653B/en active IP Right Grant
- 2013-10-25 AU AU2013334122A patent/AU2013334122B2/en not_active Ceased
- 2013-10-25 PL PL13849263T patent/PL2912013T3/en unknown
- 2013-10-25 SG SG11201503247UA patent/SG11201503247UA/en unknown
- 2013-10-25 BR BR112015009395A patent/BR112015009395A2/en not_active Application Discontinuation
- 2013-10-25 DK DK13849263.2T patent/DK2912013T3/en active
- 2013-10-25 US US14/438,323 patent/US9777038B2/en active Active
- 2013-10-25 WO PCT/US2013/066917 patent/WO2014066819A1/en active Application Filing
- 2013-10-25 NZ NZ745013A patent/NZ745013A/en not_active IP Right Cessation
- 2013-10-25 HU HUE13849263A patent/HUE036887T2/en unknown
- 2013-10-25 NZ NZ707389A patent/NZ707389A/en not_active IP Right Cessation
- 2013-10-25 CN CN201810282054.XA patent/CN108250264A/en active Pending
- 2013-10-25 ES ES13849263.2T patent/ES2655034T3/en active Active
- 2013-10-25 CN CN201380068062.XA patent/CN105102425B/en not_active Expired - Fee Related
- 2013-10-25 PT PT138492632T patent/PT2912013T/en unknown
- 2013-10-25 KR KR1020157012805A patent/KR102068381B1/en active IP Right Grant
- 2013-10-25 CA CA2889592A patent/CA2889592A1/en not_active Abandoned
- 2013-10-25 JP JP2015539862A patent/JP6272888B2/en not_active Expired - Fee Related
-
2014
- 2014-03-14 NO NO14725812A patent/NO2968302T3/no unknown
-
2015
- 2015-04-26 IL IL238454A patent/IL238454B/en active IP Right Grant
-
2016
- 2016-02-24 HK HK16102102.3A patent/HK1214239A1/en not_active IP Right Cessation
- 2016-02-24 HK HK18112593.6A patent/HK1253301A1/en unknown
-
2017
- 2017-08-21 US US15/681,609 patent/US10202414B2/en not_active Expired - Fee Related
-
2018
- 2018-01-03 CY CY20181100003T patent/CY1119731T1/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050080064A1 (en) * | 2001-03-12 | 2005-04-14 | Roberto Pellicciari | Steroids as agonists for fxr |
US20080039435A1 (en) * | 2004-02-26 | 2008-02-14 | Intercept Pharmaceuticals, Inc. | Novel Steroid Agonist For Fxr |
CN101522703A (en) * | 2006-06-27 | 2009-09-02 | 英特塞普特医药品公司 | Bile acid derivatives as fxr ligands for the prevention or treatment of fxr-mediated deseases or conditions |
CN102164940A (en) * | 2008-07-30 | 2011-08-24 | 英特塞普特医药品公司 | TGR5 modulators and methods of use thereof |
CN102282157A (en) * | 2008-11-19 | 2011-12-14 | 英特塞普特医药品公司 | TGR5 Modulators and Methods of Use Thereof |
Non-Patent Citations (3)
Title |
---|
GIOVANNI RIZZO等: "Functional Characterization of the Semisynthetic Bile Acid Derivative INT-767, a Dual Farnesoid X Receptor and TGR5 Agonist", 《THE AMERICAN SOCIETY FOR PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 * |
NORINDER, JAKOB等: "An Enantioselective Route to α-Methyl Carboxylic Acids via Metal and Enzyme Catalysis", 《 ORGANIC LETTERS》 * |
SAREL, SHALOM等: "Preparation and degradation of 3α-hydroxycholanic acid", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109069517A (en) * | 2016-04-19 | 2018-12-21 | 英特塞普特医药品公司 | The method for preparing shellfish cholic acid and its derivative difficult to understand |
CN109963567A (en) * | 2016-09-30 | 2019-07-02 | 英特塞普特医药品公司 | The crystal form of bile acid derivative |
WO2019020067A1 (en) * | 2017-07-26 | 2019-01-31 | 正大天晴药业集团股份有限公司 | Method for preparing steroid derivative fxr agonist |
CN110869381A (en) * | 2017-07-26 | 2020-03-06 | 正大天晴药业集团股份有限公司 | Preparation method of steroid derivative FXR agonist |
US20200231622A1 (en) * | 2017-07-26 | 2020-07-23 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Method for preparing steroid derivative fxr agonist |
US11059854B2 (en) | 2017-07-26 | 2021-07-13 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Method for preparing steroid derivative FXR agonist |
CN110869381B (en) * | 2017-07-26 | 2021-11-19 | 正大天晴药业集团股份有限公司 | Preparation method of steroid derivative FXR agonist |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105102425A (en) | Process for preparing bile acid derivatives | |
CN102630226A (en) | Entecavir synthesis method and intermediate compound thereof | |
CN101792486A (en) | Method for combining caspofungin acetate | |
KR101077609B1 (en) | Process for preparing tricyclic derivatives | |
CN109503624A (en) | The synthetic method of 6- oxygen subunit -8- oxa- -2,5- diaza spiro [3.5] nonane -2- t-butyl formate | |
CN110305142A (en) | A kind of Stereoselective synthesizing process of 6 beta-hydroxy morphine derivatives | |
CN112939814B (en) | Preparation method of deuterated dacarbazine intermediate | |
CN111548356B (en) | Process for preparing tert-butyl-1, 8-dioxa-4, 11-diazaspiro [5.6] dodecane-11-carboxylic acid ester | |
CN106518939B (en) | Method for preparing Solithromycin compound | |
KR20170016756A (en) | New method for preparation of chiral chromanol derivatives | |
CN1982301B (en) | A manufacturing process of 2',2'-difluoronucleoside and intermediate | |
CN110627686A (en) | Synthesis method of fluorenylmethyloxycarbonyl-O-trityl-L-threonine | |
CN109912521B (en) | Method for synthesizing alkenyl-substituted 1,2, 3-triazole derivative in one step | |
CN112028816B (en) | Synthesis method of substituted isoindoline | |
CN117865859A (en) | Preparation method of enantiomerically pure p-toluenesulfonamide | |
CN117603128A (en) | Preparation method of (3R, 6S) -3-amino-6-methylpiperidine | |
KR100234886B1 (en) | Novel process for thr preparation of 3-alkoxy-4-piperidinone derivatives | |
JPH01100147A (en) | Optically active malonic acid ester derivative | |
CN114539020A (en) | Preparation method of 1, 5-dibromo-3, 3-difluoropentane | |
JPS61221184A (en) | Production of 2-(2-thienyl)-ethylamine | |
CN110922412A (en) | Asymmetric synthesis method of medicinal compound with antipsychotic effect | |
PL213059B1 (en) | Chiral dimethylcyclopropane carboxyester and process for the preparation thereof | |
JPH0334954A (en) | Production of alkoxycarbonyl compound | |
JPS61271258A (en) | Production of optically active amino alcohol | |
JPH0429673B2 (en) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1214239 Country of ref document: HK |
|
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CP02 | Change in the address of a patent holder | ||
CP02 | Change in the address of a patent holder |
Address after: New jersey, USA Patentee after: INTERCEPT PHARMACEUTICALS, Inc. Address before: New York, United States Patentee before: INTERCEPT PHARMACEUTICALS, Inc. |
|
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180410 |